The biologic role of human intestinal intraepithelial lymphocytes (iIEL) and their functional relationship with the intestinal epithelial cell (IEC) remains incompletely characterized. Human iIELs have been variably shown to exhibit cytolytic function and possibly immunoregulatory function through the secretion of a variety of cytokines (Ebert, Clin. Exp. Immunol., 82:81-85, 1990; Lundqvist et al., J. Immunol., 157:1926-1934, 1996; Balk et al., Science, 253:1411-1415, 1991). Whether these functional activities are related to processes that may be unique to the gut associated lymphoid tissue such as oral tolerance and local immunosurveillance against IEC injury and neoplastic transformation is, however, unclear. Moreover, the molecules on the cell surface of iIELs and their IEC counterreceptors which regulate the functional activation of iIELs and which may be utilized in this special microenvironment are only beginning to be elucidated.
A significant fraction of human iIELs of both the small and large intestine are CD8-αβ+ and CD45RO+ T cells which express a limited array of αβ and, to a lesser extent, γδ-T cell receptors (TCR) (Balk et al, 1991; Jarry et al., Eur. J. Immunol., 20:1097-1103, 1990; Blumberg et al., J. Immunol., 150:5144-5153, 1993; Van Kerckhove et al., J. Exp. Med., 175:57-63, 1992; Chowers et al., J. Exp. Med., 180:183-190, 1994). These phenotypic properties indicate that iIELs are memory cells which localize to the basolateral surface of IECs for the recognition of a limited number of antigens in the context of major histocompatibility complex (MHC) class I or class I-like molecules on the IEC. However, the majority of iIELs in mouse and human are CD28− suggesting that other costimulatory molecules for TCR/CD3 complex-mediated activation may be important in providing necessary secondary signals for iIEL activation (Gelfanov et al., J. Immunol, 155:76-82, 1995; Gramzinski et al., Int. Immunol. 5:145-153, 1993; Russell et al., J. Immunol., 157:3366-3374, 1996). Candidate costimulatory molecules for human iIELs include CD2 (Ebert, Gastroenterology, 97:1372-1381, 1989), CD101 (Russell et al., 1996), BY-55 (Anumanthan et al., J. Immunol., 161:2780-2790, 1998) and αEβ7 (Parker et al., Proc. Natl. Acad. Sci., 89:1924-1928, 1992) which are expressed by the majority of iIELs.
It has also become increasingly evident that in addition to activating costimulatory molecules, T cells can express a variety of molecules that deliver an inhibitory signal such that either the initial activation of the T cell is prevented or the activated state is downregulated. The former include the killer inhibitory receptors (KIR) which are expressed on a subset of T cells and bind specific types of major histocompatibility complex (MHC) class I molecules on the target cells (Lanier et al., Immunology, 7:75-82, 1995). The latter includes CTLA-4 (CD 152) which, when expressed after T cell activation, binds either CD80 (B7.1) or CD86 (B7.2) on antigen presenting cells (Walunas et al., J Exp. Med., 183:2541-2550, 1996; Krummel et al., J Exp. Med. 183:2533-2540, 1996). These inhibitory receptors characteristically contain immunoglobulin-like domains extracellularly and one or more immune receptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic tails which consists of the consensus sequence I/L/VxYxxL/V (SEQ ID NO:5) (Véy et al., J Immunol., 159:2075-2077, 1997). In the case of CTLA-4, the ITIM is slightly modified to GxYxxM (SEQ ID NO:6) (Cambier, Proc. Natl. Acad. Sci., 94:5993-5995, 1997). ITIM-containing receptors function in the recruitment of either the Src homology domain-containing protein tyrosine phosphatases, SHP-1 and SHP-2, or the SH2 domain-containing inositol polyphosphate 5-phosphatase, SHIP (lsakov, Immunol. Res., 16:85-100, 1997). These phosphatases function in the dephosphorylation of signaling molecules recruited by immune receptor tyrosine-based activation motif (ITAM) bearing receptors like those contained in the CD3-γ,δ,ε and ζ chains that associate with the TCR. As such, ITIM bearing receptors on T cells are predicted to downregulate activation events elicited by ITAM bearing receptors if both are ligated in close proximity to one another. Importantly, neither CTLA-4 nor CD80/CD86 have been observed on human iIELs or IECs of the small intestine, respectively.